Anti diabetically active sulfonyl ureas and sulfonyl semicarbazides

ABSTRACT

NOVEL SULFONYL UREAS HAVING THE FORMULA:   X&lt;(-(1,2-PHENYLENE)-Y(-CO-NH-Z-(1,4-PHENYLENE)-SO2-NH-CO-   NH-R2)-(R1-1,2-PHENYLENE)-)   WHEREIN X REPRESENTS OXYGEN, SULFUR, SATURATED, UNSATURATED, STRAIGHT OR BRANCHED CHAIN ALKYLENE CONTAINING UP TO 3 CARBON ATOMS, OXYMETHYLENE, THIAMETHYLENE, THIAETHYLENE, IMINOMETHYLENE, ALKYLATED IMINOMETHYLENE, ACYLATED IMINOMETHYLENE, CARBOXIMIDO, ALKYLATED CARBOXIMIDO, OR A VALENCY BOND, R1 IS HYDROGEN, HALOGEN, ALKYL, ALKOXY OR TRIFLUOROMETHYL, Y IS SATURATED, UNSATURATED, STRAIGHT OR BRANCHED CHAIN ALKYLENE CONTAINING UP TO 6 CARBON ATOMS OR SUCH ALKYLENE GROUP CONTAINING A NITROGEN OR OXYGEN ATOM, Z IS STRAIGHT OR BRANCHED CHAIN ALKYLENE CONTAINING UP TO 4 CARBON ATOMS AND R2 IS STRAIGHT OR BRANCHED CHAIN, SATURATED OR UNSATURATED ALKYL OR CYCLOALKYL, AND SUCH GROUPS INTERRUPTED BY OXYGEN OR SULFUR ATOMS OR CONTAINING AN ENDO-ALKYLENE GROUP AND SUBSTITUTED OR UBSUBSTITUTED ARYL OR ARALKYL. THE AFORESAID SULFONYL UREAS CONSTITUTE EXTREMELY EFFECTIVE ANTI-DIABETIC AGENTS.

United States Patent 3,752,851 ANTI-DIABETICALLY ACTIVE SULFONYL-UREAS AND SULFONYL-SEMICARBAZIDES Werner Winter, Mannheim, Erich Fauland and Kurt Stach, Mannheim-Waldhof, Felix Helmut Schmidt, Mannheim-Neuostheim, and Walter Aumuller, Kelkheim-Mnnster, Germany, assignors to Boehringer Mannheim Gesellschaft mit beschrankter Haftung No Drawing. Original application Mar. '11, 1968, Ser. No. 711,840, now Patent No. 3,646,009. Divided and this application Sept. 21, 1971, Ser. No. 182,516 Claims priority, application Ggrmany, Mar. 15, 1967,

Int. Cl. c07c 127/00 U.s. Cl. 260-553 DA 6 Claims ABSTRACT OF THE DISCLOSURE Novel sulfonyl ureas having the formula:

wherein X represents oxygen, sulfur, saturated, unsaturated, straight or branched chain alkylene containing up to 3 carbon atoms, oxymethylene, thiamethylene, thiaethylene, iminomethylene, alkylated iminomethylene, acylated iminomethylene, carboximido, alkylated carboximido, or a valency bond, R is hydrogen, halogen, alkyl, alkoxy or trifluoromethyl, Y is saturated, unsaturated, straight or branched chain alkylene containing up to 6 carbon atoms or such alkylene group containing a nitrogen or oxygen atom, Z is straight or branched chain alkylene containing up to 4 carbon atoms and R is straight or branched chain, saturated or unsaturated alkyl or cycloalkyl, and such groups interrupted by oxygen or sulfur atoms or containing an endo-alkylene group and substituted or unsubstituted aryl or aralkyl.

The aforesaid sulfonyl ureas constitute extremely effective anti-diabetic agents.

This application is a divisional of Ser. No. 711,840 filed Mar. 11. 1968, now Pat. No. 3,646,009.

This invention relates to sulfonyl ureas and sulfonyl semicarbazides and to processes for making and using the same.

The new and valuable sulfonyl-ureas and sulfonylsemicarbazides, as they are produced according to the present invention, correspond to the following formula:

CO-NH-ZQ-SOg-NH-CO-NH-Rz (I) wherein X is oxygen, sulfur, saturated or unsaturated, straight or branched-chain alkylene containing up to 3 carbon atoms, oxymethylene, thiamethylene, thiaethylene, iminomethylene, alkylated iminomethylene, acylated iminomethylene, carboximido, alkylated carboximido, or a valency bond; R is hydrogen, halogen, alkyl, alkoxy or trifluoromethyl; Y is saturated or unsaturated, straight or branched-chain alkylene containing up to 6 carbon atoms; which can also contain a nitrogen or oxygen atom; Z is straight or branched-chain alkylene containing up to 4 carbon atoms; and R is straight or branched chain, saturated or unsaturated alkyl or cycloalkyl, which can also be interrupted by oxygen or sulfur atoms or can contain an endo-alkylene group, unsubstituted or substituted aryl or aralkyl or unsubstituted or substituted, saturated or unsaturated alkylene-imino containing 3-7 carbon atoms, which can also contain an endo-alkylene group.

A preferred group of substances within the scope of the invention are the following:

wherein R indicates hydrogen, lower alkyl or al-koxy, halogen, Z is ethylene, X indicates a valency bond, an oxygen or sulfur atom, oxymethylene, thiamethylene, thiaethylene, ethylene or vinylene, Y indicates saturated or unsaturated, straight or branched chain alkylene containing 1 to 3 carbon atoms or iminomethylene, and R indicates cycloalkyl containing 6 to 8 carbon atoms which can be substituted by 1 to 2 methyl or methoxy groups or which contain an endoalkylene group having 1 to 4 carbon atoms, alkyleneimino containing 5 to 6 carbon atoms which can be substituted by 1 to 2 methyl groups, lower alkyl, aralkyl or thiapyranyl.

The aforesaid group of compounds constitute particularly effective anti-diabetic agents.

A still more preferred group of compounds characterized by their outstanding therapeutic activity, i.e., antidiabetic effect and absence of toxicity have the Formula I as above set out, in which Formula R indicates hydrogen, lower alkyl or alkoxy, Z is ethylene, X indicates a valency bond, oxygen or sulfur atom, oxymethylene, thiamethylene or vinylene, Y indicates saturated or unsaturated alkylene containing 1 to 2 carbon atoms or iminomethylene, and R indicates cycloalkyl containing 6 to 8 carbon atoms which can be substituted by 1 to 2 methyl or methoxy groups or which can contain an endoalkylene group having 1 to 4- carbon atoms, alkyleneimino containing 5 to 6 carbon atoms or such alkyleneimino substituted with 1 to 2 methyl groups.

The most preferred group of compounds constituting the most therapeutically effective anti-diabetic agents have the Formula I above, wherein X is a valency bond, Y is methylene or ethylene, Z is ethylene, R is H, lower alkyl or alkoxy, and R is cycloalkyl containing 6 to 8 carbon atoms which can be substituted by l to 2 methyl or methoxy groups or which can contain an endoalkylene group having 1 to 4 carbon atoms, alkyleneimino containing 5 to 6 carbon atoms or alkyleneimino substituted by 1 to 2 methyl groups.

Said new compounds are obtained according to the process of the present invention by the conventional methods. Thus, for example, the following representative methods can be used:

(a) Reaction of a benzene-sulfonyl compound of the formula:

NH so Q Q (II) with a compound of the formula:

'2 wherein Q is a radical of the formula:

3.. and R R X, Y and Z indicate the same. substituents as stated above and one of the substituents U and W represents amino, and the other represents an insocyanate group or a group which is converted into an isocyanate In the case of this latter method, in place of the-urea or semicarbazide, it is more advantageous to use the corresponding parabanic acid derivative having the formula:

1 Potassium salt. Potassium salt (decomposition).

,group'under thereaction conditions. 5

Thus, for example, a sulfonamide, preferably in the 0 form offits sodium or potassium salt, is reacted with an isocyanate having the formula R -NCO, wherein R in- I -dicates the same substituents as stated above, or, alterna- HN N R1 tively a sulfo'nyl isocyanate is condensed with an apo= ;-J:=o (X) propriate amine having the formula R -NH in which R as above defiPed, Wlth an acyl denvanve thereofwherein R is as above defined, followed by hydrolysis of In place of the isocyanates, there can also be used comthe intermediate thereby obtained pounds which, under: the react1on conditions, are able to (d) Aeylation f a b fi lf l d i i h i undergo conversion into isocyanic acid esters. Illustrative 15 the formula; of the isocyanate formers of this type, which can be used within the scope of the invention, are, for example, appropriate carbamic acid halides, urethanes, thioure- (XI) thanes, ureas, as well as their acyl derivatives, disulfonyl- V ureas and the corresponding hydrazine derivatives.

(b) Hydrolysis of a benzene-sulfonyl-thi and wherem R; and Z ind cate the same substituents as stated above, with a reactive derlvatlve of an acld of the -th1osem1carbaz1de of the formula.

formula Q-OH, m which Q has the same meaning as set QNHZS02NH-CNHR2 out above.

g (V) This acylation is carried out in the conventional manwherein Q, R and Z indicate the same substituents as fi ff g macho: i g gg ig fi stated above, or of a benzene-sulfonyl-guanidine or :6 Z gzag: g g i zfigiz o a p ammo'guamdme of the formula The following examples serve to illustrate the present QNHZ-S0i-NH-JNHR, invention without, however, limiting the same thereof. tin (v1 EXAMPLE 1 wherein Q, R; and Z indicate the same substituents as stated above; or of a benzene-sulfonyl-isourea ether or 3[4'(l3'fluorene9Ylacetylammoethyn'benzene'sul -isosemicarbazide ether of the formula: fonyl]l'(4'methyl'cyclohexyl)urea Q-NH-z--s0, 4.5 g. 4-(18 fluorene 9 yl-acetylaminoethyl)-benzenet sulfonyl-carbamic acid ethyl ester 1n 100 ml. anhydrous alkyl (VII) toluene and 10 ml. dimethyl formamide were mixed, at a wherein Q, R and Z 1nd1cate the same substituents as temperature f about c with 13 1 Stated above b I Indicates an oxygen Sulfur 40 hexylamine and the resultant mixture boiled for 15 min- TbBFOIlYeTSIOB of the sulfonyl'guamdme and j utes. Thereafter, the reaction mixture was cooled and the guamqlne S Preferably brbught about by Elke-11116 solution extracted with 300 ml. 0.2 N sodium hydroxide drolysis, for eXamp1e, y means of all fllkab Pletal b solution. The sodium salt of the desired sulfonyl-urea was droxide, that of the isourea ether and lsosemicarbazide thereby precipitated The Salt was then filt d fi ether y y y as 67531111316, by mflans f 5 with suction, washed with ether and the compound disa hydrohalic acld, and that of thethiourea and thio-semrsolved, with gentle warming, in a mixture of 1 part of Carballde y OXldatlye y y as for E p y water and 1 part of acetone. Thereafter the solution was a s of nltr and or heavy metal Oxides, such as diluted with a further part of water. The thereby obtained mercury oxide. solution, which was weakly alkaline, was acidified to a Reactlon of a benzene-sulfonyl hahde of the pH of 5.5 by the addition thereto of dilute hydrochloric formula: acid. The acidification resulted in that the sulfonyl-urea Was separated out in crystalline form. Following recrystal- Q NH ZQSOFHQI (VIII) lization from methanol, the compound had a melting point wherein Q and Z are as defined above and Hat is halogen, of 198-199 C. There were recovered 3.8 g. 3- [4-(fl-fluowith a urea or semicarbazide of the formula: a i V1 g s g i" F fi U -me y-cyco exy -urea 0 o t eory). I Hz 9' 2 The compounds set out in the following Table I were wherem R has the above indicated meaning. obtained in an analogous manner:

' TABLE 1 Y Compound M.P. C. per c e ti 4-[4-(B-fluoreue-Q-yl-aeetylarninoethyD-benzene-sulfon l-1,1- 3,3-dim th I- is th 1 mi b id 4-[4-(B-fluorene-Q-yl-aeetylaminoethyl)-benzene:sultonli-1,1-E3-meth3:1-p ent ?;1 1e%h ;1en b) 2:h1i:arlf$d g? igg-igg 4-lste-gi-gg -gg lt y dro-d.\benzo-[b,e]-oxepine-11-yhdene-aeetylaminoethyl)-benzene-sulfonyl]-1,1-(3,3-dimethyl-pentamethylene)- 183-184 53 3-[4-(B-6,11-dihydro-dibenzo-[b,e -oxepme-11-y11dene-aeet lam no th 1 -b ulf 1-1- 4- th 1- l h 3-[4-(B-BJI-dihydro-dibenzo-[he -oxeptne-11-yl-aoetylami1oethyl-b51 en fl i rfyll gi-ine hy iiy lol y i) fiz f? kggg-gk-gth ydro-drbenzo-[bp -oxepine-ll-yl-acetylaminoethyl)-benzene-sulfony11-1,1-(3,S-dimethyl-pentamothylene)- 3-[4-(fi-xanthene-9-yl-acetylamtnoethyl)-benzene-sulfony1]-1-(4-methyI-cye1ohexyl)-urea 2g 4-[4-(B-xanthene-Q-yl-ecetylamrnoethyt)-benzene suliony1]-1,1-(3-methyl-pentamethylene)-semicarbazide 128-130 45 3-[4-(B-6,1 1-dihydro-d.\benzo-[b,e]-oxep1ne-1l-ylidene-2-propionylaminoethyl)-benzene-sulfonyl]-1-(4-methyl-eyelohexyD-urea. 161-163 42 4-[4-(fl-tlnaxanthene- -y1-aoetylaminoethyl)-benzene-sulfonyl]-1,1-(3,3-dimethylpentamethylene)-semicarbazide 2 172-174 55 3-[4-(B-finorene-9-yl-aeetylamtnoethyl)-benzene-su1Iony1]-1-(bicyelo-[2,2,1]-heptyl-2)-u.rea 191-193 58 3-[4-(fl-fiuorene-Q-yl-acetylamrnoethyl)-benzene-sulfonyl]-1-eyclooctyl-urea- 192-193 52 3-[4-(B-fluorene-Q-y1-aeetylaminoethyD-benzene-sulfonyl]-1-(adamantyl-1)-ur 201-202 64 3-[4-(fl-fiuorene-ti-yl-acetylaminoethyl)-benzene-sulionyl]-1-eyeloheptyl-urm 178-180 49 EXAMPLE 2 3- [4-(,B-6,1 l-dihydro-dibenzo- [b,e]-oxepine-1 l-yl-acetylamino ethyl) -benzene-sulfonyl] l-cyclohexyl-urea 4 g. 4-(18-6,1l-dihydro-dibenzo-[b,e]-oxepine-1l-yl-acetylaminoethyl)-benzene-sulfonamide, together with 2.5 g. ground potassium carbonate, in 100 ml. acetone were boiled for 30 minutes, while stirring. 1.5 g. cyclohexyl isocyanate were thereafter added in dropwise fashion and the resulting reaction mixture boiled under reflux for 2 hours, while stirring. The bulk of the solvent was then distilled off, the residue taken up in water, clarified with charcoal, filtered and the filtrate acidified with dilute hydrochloric acid. The sulfonyl-urea which thereby precipitated out was filtered 01? with suction, washed with water and recrystallized from alcohol. The sulfonyl urea had a melting point of 201-202 C. There were recovered 3.4 g. (66% of theory) 3-[4-(fi-6,1l-dihydro-dibenzo- [b,e] oxepine 11 yl acetylaminoethyl) benzenesulfonyl]-1-cyclohexyl-urea.

In an analogous manner, there was obtained 3-[4-(5- 6,11 dihydro dibenzo [b,e] oxepine 11 yl acetylaminoethyl)-benzene-sulfonyl]-1-n-butyl-urea, which had a melting point of 154-155 C., and from 4-(fi-fiuorene- 9-ylidene-acetylarninoethyl)-benzene-sulfonamide (M.P. 215-216 C.), there was obtained '3-[4-(fl-fiuorene-9-ylidene acetylaminoethyl) benzene sulfonyl] 1 cyclohexyl-urea, which had a melting point of 199-200 C.

EXAMPLE 3 3- [4- (fl-xanthene-9-yl-carboxamido-ethyl) -benzene-sulfonylJ-l-cyclohexyl-urea 6.5 g. 3-[4-(fi-arninoethyl)-benzene-sulfonyl]-1-cycloh'exyl-urea (M.P. 21!1-212 C.) were suspended in 75 ml. pyridine, mixed with 5 g. xanthene-9-carboxylic acid chloride and allowed to stand at ambient temperature for 48 hours. The solvent was then distilled off in a vacuum, the residue digested with diluted hydrochloric acid, filtered off with suction and washed with water. The crude product thus obtained was purified by dissolving in 0.2 N sodium hydroxide solution and precipitated by the addition of dilute hydrochloric acid. There were recovered 8.6 g. (81% of theory) 3-[4-(B-xanthene-9-yl-carboxamide-ethyl) -benzene-sulfonyl] -1-cyclohexyl-urea which, following recrystallization from methanol, had a melting point of 218-220 C.

In an analogous manner there was obtained 3-[4-(fl- 10,11-dihydro 5H dibenzo- [a,d] -cycloheptene-5-yl-carboxamidoethyl benzene su1fonyl]-1-cyclohexyl urea, which had a melting point of 202-203 C.

From 4-[4- (fi-aminoethyl) benzene sulfonyl]-1,1-(3- methyl-pentamethylene)-semicarbazide (M.P. 210-212 C.) and 6,11-dihydro dibenzo-[b,e]-thiepine-11-yl-acetyl chloride, there was obtained, in an analogous manner, 4- [4- (pl-6,1 l-dihydro dibenzo- [b,e]-thiepine-1 l-yl-acetylaminoethyl) benzene su1fonyl]-1,1-(3-methyl pentamethylene)-semicarbazide, which had a melting point of 222-223 C.

EXAMPLE 4 3- [4- (B-thiaxanthene-9-yl-acetylaminoethyl -benzenesulfonyl]-1-(4-methyl-cyclohexyl)-urea 4.5 g. 4-(B-thiaxanthene 9 yl-acetylaminoethyl)-benzene-sulfonamide were dissolved in 20 m1. dimethyl formamide, admixed with an equimolar amount of sodium hydride and the mixture stirred for 10 minutes at ambient temperature. Thereafter, 2.0 g. pyrocarbonic acid diethyl ester were added, and then 10-15 minutes later 0.36 g. hydrogen chloride, dissolved in a little absolute ethanol was added to the resultant solution. The solution thus obtained of 4-(,B-thiaxanthene-9-yl-acetylaminoethyl)-benzene-sulfonyl-ca-rbamic acid ethyl ester was mixed with 1.4 g. 4-methyl-cyclohexylamine in ml. toluene and this reaction mixture then boiled for 25 minutes. After cooling, the reaction mixture was extracted with 0.2 N sodium hydroxide solution and the desired sulfonyl-urea thereafter precipitated out by the addition of dilute hydrochloric acid. There were recovered 3.2 g. (55% of theory) 3-[4-( 8-thiaxanthene-9-yl-acetylaminoethyl)-benzene-sulfonyl]-1-(4-methyl cyclohexyl)-urea which, following recrystallization from methanol, had a melting point of 198-199 C.

EXAMPLE 5 3- [4- B-fluorene-9-yl-acetylaminoethyl) benzenesulfonyl] -1- (4-methoxy-cyclohexyl -urea 8.6 g. of the sodium salt of 4-( s-fluorene-9-yl-acetylaminoethyl)-benzene-sulfonamide were suspended in 20 ml. dimethyl formamide, 4.0 g. pyrocarbonic acid diethyl ester were added thereto and, following completion of the reaction which then took place, the reaction mixture was mixed with 0.73 g. hydrogen chloride in a little absolute ethanol. Thereafter, 3.3 g. 4-methoxy-cyclohexylamine in ml. toluene were added and the resultant reaction mixture boiled for 15-20 minutes. The further working up of the reaction mixture was carried out as described in Example 4. After recrystallization of the crude product from methanol/dimethyl formamide/water (2:1:2.5), there were obtained 6.8 g. (61% of theory) 3-[4- (B-fluorene-9 yl acetylaminoethyl)-benzene-sulfonyl]-1-(4-methoxy-cyclohexyl)-urea, which had a melting of 196-197 C.

The compounds set out in Table II, which follows, were prepared in an analogous manner to that described in Examples 4 and 5:

TABLE II Prepared according M.P. Yield,

Compound to example in 0. percent 4-[4-(B-thiaxanthene-Q-yI-acetylaminoethyl)-benzene-sulfonyl]-1 ,1-(B-methylpentamethylene) -semicarbazl de 4 175-176 48 3-[4-(B-fluorene-Q-yl-acetylamrnoethyl)-benzene-sulf0nyl]-1-(tetrahydro-thiapyranyl-4)-11rea. 5 221-222 53 3-[4-(,S-fluorene-9-yl-acetylam1noethyl)-benzene-sulfonyl]-1-(4, 4-dimethy1-eyclohexyl)-urea 5 197-198 67 3-[4-(B-fiuorene-Q-y1-acetylam1noethy1)-benzene-suliony1]-1-(fi-phenyl-ethyD-urea 5 186-187 55 4-[4-(B-fluorene-9-yl-acetylaminoethyl)-be1mene-sulfonyl]-1,1-hexamethylene-semicarbazide 5 110-112 72 4-[4-(IS-fluoreue-Q-ylideneaeetylamlnoethyl)-benzene-sulfonyl]-1,1-(3-methyl-pentamethylene)-semjcarbazide 4 -156 63 3-[4-( 3-6,l1-d1hydr0-d1benzo-[b,c]-th1epine-1l-ylideneacetylaminoethyl)-benzene-sulionyl]-1-(4-methyl-cyclohexy1)- urea- 4 189-190 70 4-[4-(6-6, 11-dihydro-dibenzo-[b,e]-th.iepil1e-11-ylideneacetylaminoethyl)-benzene-sulfonyl]-1,1-(3-methyl-pentamethylena)-sem.iearha irln 4 210-211 74 3-[4-(B-fluorene-9-y1idens-acetylaminoehtyb-benzene-sulfony1]-1-(4-methy1-cye1ohexyl)-urea 4 210-212 72 3-[4-(B-fluorene-9-acetylaminoethyl)-benzene-sulfonyl]-1-cyclohexyl-urea 5 204-205 54 3-[4-(B-5H-dibenzo-[a, d] eyeloheptene-5-yl-acety1aminoethyl)-benzene-sultonyl]-1-(4-methylcyclohexyl)-urea 4 174-175 67 3-[4-(fl-12H-6,7-d1hydro dibenzo-[b ,e]-th1oc1ne1Z-yI-acetylaminoethyl)-benzene-sulfonyl]-1-(4-methyl-eyclohexyl)-urea 4 184-186 71 3-[4-(B-earbazol-9-yl-acetylaminoethyl)-bemene-sulfonyH-l-cyelohexyl-urea 4 196-198 64 3-[4-(B-carbazol-9-y1-acetylaminoethyl) -benzene-sulfonyLI-l-(4-methyl-cyclohexyl)-urea 4 198-200 73 4-[4-(B-carbazol-Q-yl-acetylaminoethyl)-b enzene-sulfonyl -1,1- (3-methyl-pentamethylene)-semicarbazi de- 4 154-156 58 3-{ 4-[6-(fi-carbazol-9-yl-prop1onylamino)-ethyl]-benzene-sulfonyl }-1-( l-methyI-cyclohexyl)-urea 4 206-208 63 3-[4-(6511-10,11-dihydro-dibenzo-[a,d]-eyeloheptene-S-ylidene-acetylaminoethyl)-benzene-sulfonyl]-l-(4-methy1- pantamethylene)-semicarbazid 4 226-228 50 4-[4-(fl-6,11-dihydro-dibenzo-[b,eloxepine-ll-yl-acetylaminoethyl)-benzene-sulfonyl]-1,1-(3-methy1- pentamethylene)-semicar 4 198-200 48 TABLE II-Continued Prepared according M.P. Yield, Compound to examplein 0. percent 3-[4-(B-fluorene-9-yl-carboxamido-ethyl)-benzene-sulfonyl]-1-cyclohexyl-urm 4 207-208 55 3-[4- (B-fluorene-Q-yl-carboxami doethyl)-benzene-sulfony1] -1- (4-methyl-cyclohexyl) -urea 4 224-226 75 4-[4-(B-fluorene-9-yl-carboxamido-ethyl) -benzene-sulfonyl]-1.1-(3-methyl-pentamethylene) -sem.icarbazi de 4 172-178 62 3-[4- (B-fluorene-Q-yl-propionylaminoethyD-b enzene-sulfonyl]-1-cyclohexyl-ur 4 207-208 60 3-[4-(B-fluorene-g-yl-propionylaminoethy1)-benzene-sulfonyl]-1-(4-methyl-cyclohexyl)-urea 4 210-212 59 4-[4- (fl-fiuorene- -yhpmpionylaminoethyl) -benzene-sulfonyl]-1,1-(3,3-(1imethyl-pentamethylene)-sernicarbazide 4 156-158 52 3-[4- (fl-2-methoxy-6,1l-dihydrodib enzo-[b,e]-oxepine-1l-yl-acetylarninoethyl)-benzeue-sulf0nyl]-ll-methylcyclohexyl) -ureap 4 172-174 67 3-[4-(B-2-methyl-6,11-dihy dro dibenzo-[b,e]-oxepine-ll-yl-acetylamlnoethyl)-l)enzene-sulfonyl]-1-(4-methylcyclohexyD-urea. 4 179-180 56 3-[4- (fl-2-cl1loro-6,11-dihydrodibenzo-[b,e]-oxepine-11-y1-acetyl ammoethyl)-benzene-sulfonyl]-1- (4-methylcyelohexyl) -urea- 4 210-212 72 8-[4-(Be-methyl-Iluorene-9-yl-acetylarninoethyl)-benzene-sulfonyl]-1-(4-methy1-cyclohexy1)-urea 4 202-203 75 3-[4-(B-3-meth0xy-fluoreue-9-yl-acety1an1inoethyl) -benzene-sulionyl]-1- (4-rneth yl-cyclohexyl) -urea 4 168-160 58 3-[4-(fl-2-chloro-fiuorene-Q-yl-acetylaminoethyl)-benzene-sulf0nyl]-1-(4-rnethyl-cyclohexyD-urea 6 218-220 6 The compounds required for use as starting materials can be prepared according to the following methods:

(a) Acylaminoethyl-benzene-sulfonamides formamide, mixed with 1 mol sodium hydride, while cooling, and then stirred for 20 minutes at ambient temperature. The resultant reaction mixture was then mixed with 1.2 mol pyrocarbonic acid diethyl ester and heated, while stirring, to C. After subsidence of the evolution of carbon dioxide, the solvent was distilled off in a vacuum, the residue dissolved in a large quantity of water and the carbamic acid ester thus obtained precipitated out by acidifying, while stirring, with dilute hydrochloric acid to a pH of about 3-4. If desired, the product obtained could be recrystallized from alcohol.

In the following Table III, there are set out a number of benzene-sulfonamides and benzene-sulfonyl-carbamic acid esters prepared in the above-described manner. The melting points of the initial tricyclic carboxylic acids (Q.OH) are given in the first column of this table.

TABLE 111 MP. of Q-OH MP in C. R in C.

229-231 Fluoreue-Q-ylidene-acety H 215-216 139-141.-- Fluorene-Q-yl-acety' {5 igfigg 158-159 Xanthene-Q-yl-aeety {ECOOCzHH 170-171 Thiaxanthene-Q-yl-acety COOCzHb 185-186 6, 1l-dihydro-dibenzo-[b,e]-oxepine-ll-ylidene-acetyl l COOCzH5 gggjg? 117-119 6,l1-d.ihydro-dibenzo-[b,e]-oxepine-11-y1-acetyl H 178-179 178 6,1l-dihydro-dibenzo-[b,e]-oxepine-1l-ylidene-Z-propiouyl COOC2H 128-130 6,11-dihydro-dibenzo-[b,e]-thiepiue-11-ylidene-acety1. H 210-212 6,11-dihydro-dibenzo-[b,el-thiepine-ll-yl-acet H 167-169 6,7-dihydro-12H-dibenzo-[b,e]-thiocine-12-ylidene-acetyl 6,7-dihydro-12H-dibeuzo-[b,e]-thiocine-12-y1-acetyl H 163-165 6-oxo-5,6-dihydro-l1H-dibenzo-[b,e]-azepine-ll-yl-acetyl 10,11-dihydro-5H-dibenzo-[a,d]-eycloheptene-5-yl-acetyl- H 194-195 Oarbazol-Q-yl-aeetyl H 254-255 B-(carbazol-9-yl)-propionyl H 173 Fluorene-Q-yl-carbonyl. H 234-236 B-(fluorene-9-yl)-propionyl H 186-188 126-127 3-mcthyl-fluorene-9-yl-acetyl H 210-211. 170-171.-. 3-methoxy-fiuorene-Q-yl-acetyl, H 158-160 2-chlorofluorene-9yl-acetyl H 212-213 119-120. 2-methoxy-6,1l-dihydrodibenzo-[b,e]-oxepineyl-acety H 138-140 110-111. Z-methyl-G,ll-dihydrodibenzo-[b,e]-oxepine-11-yl-acetyl H 169-170 211-212..- 2-ch1oro-6,ll-dzhydrodibenzo-[b,e]-oxepine-11-y1-acetyl H 190-193 salt. This salt was brought to solution by the addition of a dilute solution of sodium hydroxide and dilution with water (pH of about 10-11), the methylene chloride separated off and the 4-(fi-acylaminoethyl)-benzenesulfonamide precipitated out by the addition to dilute hydrochloric acid to a pH of about 8.8. If desired, the product could be recrystallized from dilute alcohol or from alcohol/dimethyl formamide/water (about 10:1:6).

(b) Acylaminoethyl-benzene-sulfonyl-carbamic acid esters '1 mol of the acylaminoethyl-benzene-sulfonamide ob- The blood sugar reducing activities of some of the,

new sulfonyl areas and sulfonyl semicarbazides were determined. The blood sugar reducing activity was measured in the rabbit following the i.v. administration of blood sugar level. The values as reported in the table which follows are relative values based on N -(sulfaniltained according to (a) above was dissolved in dimethyl yl)-N -(n-butyl)urea equal to 1. The threshold-dose of the N -(sulfanilyD-N -(n-butyDurea amounted in this series with a suitable pharmaceutical diluent is employed. One

of tests to 200 mg./kg. or two unit dosages are good from one to four times The results are set forth in the following table. a day.

TABLE Relative blood sugar re ueing activity (rab- Compound bit I.V.)

3- 4-(fi-fiuorene-9-yl-acetyl-aminoethy1)-benzene-sulfonyl -1-(4-methyl-cyclohexyl) -urea 8, 000 4- 4-(fl-fluorene-Q-yl-acetyl-aminoethyl)-benzene-sulfonyl]-1,1-(3,3-dimethyl-pentamethylene)-sem.icarbazide 16. 000 4- 4-(B-fluorene-9-yl-acetyl-aminoethyl)-benzene-sulfonyl]-l,I-(S-methyl-pentamethylene)-semicarbazide 16. 000 4-[4-(%-6, 1-dihydro-dibenzo-[b,e]-oxepine-11-yl1dene-acetyl-aminoethyl)-benzene-sultonyl]-1,1-(3,3-dimethyl-pentamethylene)sem:l- 2 000 car 821 e 3- 4-(B-6,11-dihydrodibenzo-[b,e]-oxepine-1l-ylidene-aoetyl-aminoethyl)-benzene-sulfonyl]1-(4-methy1cyclophexyl)-u.rea 800 3- 4-(5-6,l1-dihydro-dlbenzo-[b,e%-oxepine-1l-yl-acetyl-azninoethyl) -benzene-sulfonyl]-l-(4-methylcyelohexyl) -urea 800 4- 4-(%-6,l-dihydro-dibenzo-[b,e -oxepine-ll-yl-acetyl-aminoethyl) -benzene-sulfonyl]-1,l-(8,3-dimethyl-pentamethylene)-serni- 2 000 car an e 3-[4-(B-xanthene-9-yl-aeetyl-aminoethyl) -benzene-snlfonyl]-1-(tmcthyl-cyclohexyl) -urea 2, 000 4-[4-(B-xanthene-Q-yl-aeetyl-aminoethyl)-benzene-sulfonyl]-1,1-(B-methyl-pentamethylene)-semicarbazide 400 4-[4-(B-thiaxanthem-9-yl-acetyl-aminoethyl)-benzene-sulfouyl]-1,1-(3,3-d1rnethyl-pentamethylene)-semicarbazide 2. 000 3-[4-(fl-fluorene-Q-yl-acetyl-aminoethyl) -benzene-sulfonyH-l-(bieyclo[2,2,ll heptyl-2) -urea 4. 000 3-[4-(fl-fluorene-9-yl-acetyl-aminoethyl)-benzene-sulfonyl}-1-cyclooctyl-nrea 4. 000 3-[4-(B-fluorone-9-y1-acetyl-aminoethyl)-benzene-sulfonyl -1-(adamanty1-1)-urea 4. 000 3-[4-(B-fluorene-Q-yI-acetyl-aminoethyl)-benzene'sulionylh-oycloheptylurefl 4. 000 3-[4-09-6,11-dihydro-dibenzo-[b,e -oxepine-11-yl-acetyl-aminoethyl)-benzene-sulfonyl]-l-eyclohexyl-urea 2. 000 3-[4-(645,11-dihydro-dibenzo-[b,e -oxepine-11-yl-acetyl-aminoethyl)-benzenesulfonyll-l-n-butyburea 200 4-[4-(B-6Jl-dihydro-dibenzo-[b,el-thiepine-ll-yl-acetyl-armnoethyl)-benzene-sulfonyll-l,l-(3-methyl-pentamethyleno)semicarbazide 800 3-[4-(B-thiaxanthene-9-yl-acetyl-aminoethyl)-benzene-su1fony1]-1-(4-methyleyclohexyD-urea 2, 000 3-[4-(B-fiuorene-9-yl-acetyl-aminoethyl)-benzene-sulfonyl]-1-(4-methoxy-cyclohexyl)-urea. 4, 000 4-[4-(B-thiaxanthene-9-yl-acetyl-aminoethyl)-benzene-sulfonyl]-1,1-(ii-methyl-pentamethylene)-semiearbazide o 3-[4-(B-fluorene-Q-yl-acetyl-aminoothyl)-benzene-sulfonyl]-1-(tetrahydro-thiapyranyl-4)-ur 800 3-[4-(B-fiuorene-9-yl-aeetyl-aminoethyDbenzene-sulionyl]-1-(4,4-dimethyl-cyclohexyl)4mm 4' mg 3-[4-(B-fiuorene-9-yl-aeetyl-aminoethyl)-benzene-sulfonyl}-l-(B-phenyl-ethyl)-urea. 400 4-[4-(fl-fluorene-Q-yl-aeetyl-aminoethyl) -benzene-sulfonyl1-l,1-hexamethylene-semicarbazido. 16 000 3-[4-(5-6,11-dihydro-dibenzo-[b,e]-thiepine-1l-ylidene-aoetyl-aminoethyl)-benzene-sulfonyl]-l-(4-methyl-oyclohexyD-urea 800 4-[4-(8-6,11-dihydro-dibenz0-[b,e]-thiepine-1l-y1idene-acetyl-aminoethyl)-benzene-sulfonyl]-1,1-(3-methyl-pentamethylene) -semicarbazide 2, 000 3-[4-(B-fiuorene-Q-yl-aeetyl-aminoethyl) -benzene-sulionyl]-1-cyelohexylur 8, (100 3-[4-(fi-sH-dibsnz-[a,d]-eycloheptene-5-yl-aeetyl-aminoethyl)-benzene-sulfonyl]-1-(tmethyl-eyclohexyl)-urea 2, 000 344-(fl-12H-6,7-dihydro-dibenzo-[b,e]-thiooine-12-yl-acetyl-aminoethyl)-benzene-sulfonyl]-1-(4-methyl-cyelohexyl)-urea 400 3-[4-(fl-earbazol-Q-yl-acetyl-a1ninoethyl)-benzene-su1fonyl]-1-oyelohexyl-ur 2, 000 3-[4-(fi-carbazol-Q-yl-acetyl-aminoethyl)-benzene-sulfonyl]-l-(4methyl-cyclohexyl)-urea 800 4-[4-(Bparbazol-Q-yl-aeetyl-aminoethy1)-benzene-su1fony1]-1,l-(3-methyl-pentamethylene)-semicarb azide 2, 000 3-[4-(19-5H-l0,11-dihydro-dibenzo-[a,d]-eyeloheptene-5-ylidene-acetyl-aminoethyl)-benzene-sulfonyl]-1-(4-methyl-eyclohexyl)-urea 800 3-[4-(B-SH-l0,1l-dihydro-dibenz0-[a,d}-eyelohepteno-o-yl-acetyl-amlnoethyl)-benzene-su1ionyl]-1-(4-methyl-eyelohexyl)-urea 800 4-[4-( s-6,11-dihydro-dibenzo-[b,e]-thiepine-1l-yl-acetyl-aminoethyl)-benzene-sulfonyH-l-(4-methyl-cyclohexyl)-urea 400 4-[4-(fl-6.l1-dihydro-dibenzo-[b,e]-thiepine-l1-yl-acetyl-aminoethyl) -benzeI1e-sulfonyl]-l,1-(3,3-dimethyl-pentarnethylene) -semicarbazide 800 4-[4- (pi-6,1l-dihydro-dibenzo-[b,e]-oxepine-11-yl-acetyl-aminoethyl) -benzene-sulfonyl]-1,1 (3-methyl-pentamethylene) -semi carb azide 2, 000 3-[4-(fl-fiuorene-Q-yl-carboxami(lo-ethyl)-benzeno-su1fonyl]-1-cyclohexyl-urea 4, 000 3-[4-(B-fiuorene-9-yl-oarboxamido-ethyl)-benzene-sulfony1]-1-(4-methyl-cyclohexyD-urea 3, 000 3-[4-( s-311mmyl-fluomne-Q-yl-acetyl-aminoethyl)-benzene-sulfonyl]-1-(4-rnethyl-cyclohexyl)-mea 4, 000 -[4-(B 3-m thoxy-fiuorens-9-yl-aeetyl-aminoethyl)-benzene-sulionyl]-1-(4-methyl-eyelohexyl)-urea 4,

In normal clinical use, the compounds can be employed in both the free and the salt form. The activity of the compounds is independent of whether they are in salt form or otherwise. Salts may be prepared by any of the wellknown standard methods. While the salt normally employed is the alkali salt and preferably the sodium salt, the compounds have been prepared in the form of other salts, such as potassium, ammonium, etc.

The products of this process may be combined with a pharmaceutical carrier for administration to humans in an amount to attain the desired blood sugar reducing efiect. Such carriers are either solid or liquid. Exemplary of solid pharmaceutical carriers are lactose, cornstarch, mannitol, talc, etc. The compounds 'of this invention are mixed with a carrier and filled into hard gelatin capsules or tabletted with suitable tabletting aids, such as magnesium stearate, starch, or other lubricants, disintegrants or coloring agents. It combination with a liquid carrier is desirable, a soft gelatin capsule is filled with a slurry or other dispersion of the novel compounds in soya-bean, corn or peanut oil. Aqueous suspensions or solutions are prepared for alternate, oral or parenteral administration.

The dosage of the novel compounds of the present invention for the treatment of diabetes depends in the main on the age, weight, and condition of the patient being treated. The preferable form of administration is via the oral route in connection with which dosage units containing 5-500 mg. of active compound in combination What is claimed is: 1. A compound having the formula:

wherein X is selected from the group consisting of oxygen. sulfur, ethylene, vinylene, oxymethylene, thiamethylene, thiaethylene, and a valency bond; R is selected from the group consisting of hydrogen, chloro, methyl and methoxy; Y is selected from the group consisting CH-, CHCH CHCH --CH C=CH-, and NCH with the proviso that X and Y cannot both contain a hetero atom and the further proviso that the ring containing X and Y contain no more than 8 ring atoms; Z is selected from the group consisting of straight and branched chain alkylene containing up to 4 carbon atoms; and R is selected from the group consisting of cycloalkyl containing 6 to 8 ring carbon atoms which may be substituted by 1 to 2 methyl or methoxy groups, bicyclo[2,2,1]-heptyl-2, adamantyl, lower alkyl, phenyl loweralkyl wherein the alkyl group contains up to 2 carbon atoms and tetrahydrothiapyranyl.

'1 1 12 2. A compound according to claim 1 wherein Z is Referen es Cited ylene. UNITED STATES PATENTS 3. A compound according to claim 1 designated 3-[4- (B fluorene 9 y1 acetybaminoethy1) benzenesulfonyl1 Aumuller at al. X

1-(4-methyl-cyclohexyl)-urea.

4. A compound according to claim 1 designated 3-[4- 5 BERNARD HELFIN Pnmary Exammer (p fluorene 9-y1-carboxamido-ethyl)-benzenesulfony11- G. A. SCHWARTZ, Assistant Examiner 1-(4-methy1-cyclohexy1') -urca. e

- 5. A compound according to claim 1 designated 3-[4- US. Cl. X.R.

( 3 -fluorene 9 yl-acetylaminoethyl)-benzenesulfony1]- 10 3293 327 B, 333, 327 B, 293.54, 239 D,

293.57 293.58, 293.5 1 2 '6. A'compound according to claim 1 designated 3-[4- 8 (p fluorene 9 yl-acetylaminoethyl)-benzenesu1fonyl]- l-cyclohexylurea. 

